Project Summary Bacterial exacerbations cause significant morbidity and mortality and account for 70-80% of COPD-related health care costs. COPD patients exhibit steroid resistance and therefore, inhaled corticosteroids show only modest effects in reducing COPD exacerbations. Currently, there are no effective therapies to prevent COPD exacerbations. Oxidative stress plays a central role in the pathogenesis of COPD exacerbations by impairing pulmonary anti-bacterial innate immune defenses and augmenting inflammatory responses in lung epithelial cells and alveolar macrophages of COPD patients by inducing epigenetic chromatin modifications via altered HDAC2 activity. Our laboratory has established that the transcription factor Nrf2 is a major regulator of an adaptive response that counteracts oxidative stress, inflammation and host defense in lungs of cigarette smoke exposed mice and COPD patients. Deficiency of the transcription factor, Nrf2, impairs host defense and augments oxidative stress and emphysema in CS-exposed mice, while lungs of COPD patients show diminished Nrf2 activity. On the contrary, augmenting Nrf2 by a small molecule attenuates pulmonary innate immune dysfunction, inflammation, and alveolar destruction and improves steroid sensitivity in CS-exposed mice. Broccoli sprouts contain sulforaphane, which is a potent activator of Nrf2. Evidence from several animal and human studies have demonstrated antioxidant, anti- inflammatory and anti-cancer properties of broccoli sprout extract (BSE) or sulforaphane, which is largely mediated by enhancing the Nrf2 pathway. We have completed testing of GMP-manufactured BSE on 65 COPD patients for determining safety and dose tolerance. In this application, we will evaluate whether dietary supplementation of BSE attenuates bacterial exacerbations in preclinical models. We will investigate the mechanisms by which BSE improves pulmonary anti-bacterial defenses and corticosteroid sensitivity and protects from alveolar destruction in mice exposed to chronic cigarette smoke. We will identify proof-of- mechanism PD biomarkers of Nrf2, which could be translated to clinical trial. Successful completion of our proposed research will help us in designing a definitive clinical trial for prevention of COPD exacerbations.